Project Summary/Abstract Ototoxicity, a leading cause of acquired hearing loss from pharmacotherapeutic agents worldwide, has become an epidemic in pediatric and adult populations. National guidelines by the American Academy of Audiology and American Speech-Language-Hearing Association recommend serial monitoring of behavioral pure-tone thresholds (PTTs) and physiologic-based measures to monitor ototoxicity. However, evidence-based research shows that ototoxic monitoring is not a consistent practice for patients in US clinics, partly due to lack of physician and patient knowledge about the onset and effects of ototoxicity. Physiologic-based tests are critically needed for obtaining information about auditory function in a time-efficient manner, particularly in chronically ill patients and in pediatric populations who are unable to complete reliable PTT testing. In the US, persons with cystic fibrosis (CF) are at high risk for developing ototoxicity due their lifelong treatments with intravenous (IV) aminoglycoside (AG) antibiotics. These medications are often used because of their cost-effectiveness and high bacterial efficacy for treating life-threatening lung infections. Unfortunately, these treatments may have detrimental effects on hearing, often producing permanent high- frequency sensorineural hearing loss. Only 26% of CF clinics across the country routinely monitor hearing for ototoxicity, and protocols that do exist rely on time consuming PTT hearing assessments that may be unrealistic in this often ill population. This is an ideal cohort for which to develop an efficient, cost-effective and reliable ototoxic monitoring protocol including physiological measures, given their lifelong use of AG therapy and lack of consistent hearing monitoring. A fast, accurate physiological test to identify patients at high risk for developing ototoxicity or permanent hearing loss would address a major clinical need across all populations. National guidelines recommend a physiologic-based method to accompany behavioral testing, however a reliable measure predictive of PTT changes has not been established. Otoacoustic emissions (OAEs) are often used to determine cochlear integrity, however the magnitude of change for these responses has not shown good predictability for shifts in PTTs. Therefore, it is critical to investigate other objective clinical tests that may improve predictability of permanent hearing loss. The medial olivocochlear (MOC) system is an efferent- mediated reflex thought to control cochlear gain by modifying outer hair cell activity in frequency ranges important for processing speech. Human and preclinical evidence suggests that efferent fibers are impaired by ototoxic treatments, prior to outer hair cell loss. Preclinical (animal) research shows that (i) AGs cause dose- dependent reductions of OAE levels and (ii) loss of MOC-mediated inhibition from AGs is predictive of SNHL. The purpose of this proposal is to establish the clinical utility of physiological measurements of MOC inhibition in combination with OAEs for identifying early indicators of ototoxicity. The novel aspects of this study are to utilize the MOC response to: (i) provide new knowledge about how ototoxic drugs affect the pathophysiology of the cochlea, (ii) determine if MOC inhibition provides a more sensitive measure of ototoxic damage than OAEs alone, and (iii) provide direction for the use of an optimal physiologic-based test method of ototoxicity, particularly for pediatric patients who may be more difficult to test with behavioral methods than adults. A longitudinal study design will be used to measure transient-evoked (TE)OAEs in quiet, and with contralateral acoustic stimulation (CAS) to activate MOC inhibition. CF patients from an established cohort of ~150 patients, aged 15+ yr. old, will be recruited. Seventy normal hearing CF patients will participate in this study (35 treated with IV-AGs and 35 without a history of IV-AG treatments). This research will examine differences in TEOAE and MOC inhibition for both CF groups. Findings will be compared to an age-, gender- and hearing-matched control group (N= 30) without CF or history of IV-AG treatments. The primary aim of this study is to determine the relationship between TEOAEs, MOC inhibition and PTTs in these three groups. The effects of cumulative IV-AG dosing will also be examined in the CF group receiving treatments. The outcome of this research will identify characteristic changes of the auditory system associated with ototoxicity in CF patients. The long-term goal of this research is to provide direction for an optimal physiologic-based test protocol to be used for ototoxic monitoring, particularly for chronically ill patients and for pediatric patients who are unable to respond to behavioral tests.